Cytotoxic T lymphocytes (CTLs) play critical antitumor roles, encompassing diverse subsets including CD4+, NK, and γδ T cells beyond conventional CD8+ CTLs. However, definitive CTLs biomarkers remain elusive, as cytotoxicity-molecule expression does not necessarily confer cytotoxic capacity. CTLs differentiation involves transcriptional regulation by factors such as T-bet and Blimp-1, although epigenetic regulation of CTLs is less clear. CTLs promote tumor killing through cytotoxic granules and death receptor pathways, but may also stimulate tumorigenesis in some contexts. Given that CTLs cytotoxicity varies across tumors, enhancing this function is critical. This review summarizes current knowledge on CTLs subsets, biomarkers, differentiation mechanisms, cancer-related functions, and strategies for improving cytotoxicity. Key outstanding questions include refining the CTLs definition, characterizing subtype diversity, elucidating differentiation and senescence pathways, delineating CTL-microbe relationships, and enabling multi-omics profiling. A more comprehensive understanding of CTLs biology will facilitate optimization of their immunotherapy applications. Overall, this review synthesizes the heterogeneity, regulation, functional roles, and enhancement strategies of CTLs in antitumor immunity, highlighting gaps in our knowledge of subtype diversity, definitive biomarkers, epigenetic control, microbial interactions, and multi-omics characterization. Addressing these questions will refine our understanding of CTLs immunology to better leverage cytotoxic functions against cancer.

中文翻译：

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CTL 异质性和可塑性：对癌症免疫治疗的影响

细胞毒性 T 淋巴细胞 (CTL) 发挥着重要的抗肿瘤作用，除了传统的 CD8+ CTL 之外，还包括不同的亚群，包括 CD4+、NK 和 γδ T 细胞。然而，明确的 CTL 生物标志物仍然难以捉摸，因为细胞毒性分子表达不一定具有细胞毒性能力。尽管 CTL 的表观遗传调控尚不清楚，但 CTL 的分化涉及 T-bet 和 Blimp-1 等因子的转录调控。 CTL 通过细胞毒性颗粒和死亡受体途径促进肿瘤杀伤，但在某些情况下也可能刺激肿瘤发生。鉴于 CTL 的细胞毒性因肿瘤而异，增强这一功能至关重要。本综述总结了当前关于 CTL 子集、生物标志物、分化机制、癌症相关功能以及改善细胞毒性策略的知识。关键的悬而未决的问题包括完善 CTL 定义、表征亚型多样性、阐明分化和衰老途径、描述 CTL-微生物关系以及实现多组学分析。对 CTL 生物学的更全面的了解将有助于优化其免疫治疗应用。总的来说，这篇综述综合了 CTL 在抗肿瘤免疫中的异质性、调控、功能作用和增强策略，强调了我们在亚型多样性、明确的生物标志物、表观遗传控制、微生物相互作用和多组学表征方面的知识差距。解决这些问题将加深我们对 CTL 免疫学的理解，从而更好地利用细胞毒功能来对抗癌症。